Abstract:

The present invention is related to a method to obtain reactive [18F]
fluorides in an organic medium suitable for radiolabelling without any
azeotropic evaporation step, by the use of a solid phase extraction
column containing a modified non-ionic solid support.

Claims:

1. A method to extract out of an aqueous solution, concentrate and/or
reformulate [18F] fluorides without any evaporation step, in particular
without any azeotropic evaporation step, said extraction, concentration
and/or reformulation process comprising the following steps of:passing
said aqueous [18F] fluoride solution through a solid phase extraction
column containing a modified non-ionic solid support (SS) so that that
said [18F] fluorides are trapped on the solid support,optionally purging
the SS with a neutral solvent or flushing the SS with a gas, to remove
most of the residual water,eluting the [18F] fluorides in an organic
solvent or in a mixture of organic solvents suitable for
radiolabelling,characterised in that said modification of the non-ionic
SS has been performed prior to the [18F] fluoride extraction process, by
causing the adsorption of a trapping agent (TA) on the SS, said TA being
selected for its ability to trap the [18F] fluoride in an anion exchange
process so that to form a TA-[18F] species, itself able to remain
adsorbed on the SS, the couple SS-TA being selected in such a way that
most of the TA is able to remain on the SS during the transit of the
aqueous [18F] fluoride solution through the column, while being easily
eluted in an organic solvent or in a mixture of organic solvents suitable
for radiolabelling.

2. Method according to claim 1, characterised in that the SS is selected
from the group consisting of extraction resins and liquid chromatography
resins comprising polar and non-polar phases.

4. Method according to claim 3, characterised in that said phases
functionalized with or made of alkyl chains are selected from the group
consisting of C2, tC2 C4, C8, C18, tC18 and C30.

5. Method according to claim 1, characterised in that the SS is selected
from the group consisting of solid phase extraction resins and liquid
chromatography resins having an intermediate polar/non-polar and/or a
hydrophilic/lipophilic character.

6. Method according to claim 5, characterised in that said character(s)
result(s) from the copolymerization of divinylbenzene and/or styrene, or
the surface functionalization of preformed beads made of (co)polymers of
divinylbenzene and styrene by the copolymerization with a vinyl
co-monomer.

13. Method according to claim 11, characterised in that a complexing agent
is functionalized by a substituting group, selected from the group
consisting of an alkyl chain comprising from 1 to 30 carbon atoms,
preferably from 1 to 16 carbon atoms, an aryl group such as benzyl,
cycles such as cyclohexane, cyclooctane, polycycles such as naphthalene,
a polymer and any moiety having a chemical function with specific binding
properties toward said SS.

14. Method according to claim 13, characterised in that said substituting
group is branched on one or several carbon atoms of an alkyl chain.

15. Method according to claim 13, characterised in that said alkyl chain
is substituted by halogen atoms on one or several carbon atoms of said
alkyl chain, preferably is a perfluorinated alkyl chain.

16. Method according to claim 10, characterised in that the TA is an
ammonium salt, preferably a quaternary ammonium salt or a phosphonium
salt, preferably a quaternary phosphonium salt or a sulfonium salt.

17. Method according to claim 16, characterised in that the TA is an
asymmetric quaternary ammonium or phosphonium salt, preferably with R1,
R2, R3 alkyl chains so that R1=R2=R3, R4 being a longer alkyl chain than
R1 or with at least a perfluorinated alkyl chain.

18. Method according to claim 17, characterised in that R1, R2 and R3 have
1 to 4 carbon atoms and R4 has 7 to 18 carbon atoms.

20. Method according to claim 11, characterised in that the preparation is
performed in two steps, the first one consisting of adsorbing a
complexing agent, the second one being the complexation of the metal salt
by the complexing agent previously trapped on the SS, the anion present
on the support being possibly converted by an anion exchange process on
TA-modified SS.

21. Method according to claim 1, characterised in that it comprises a
purging step in which a protic solvent such as alcohol is passed through
the column to eliminate most of the remaining water, whilst keeping the
extracted anions trapped on the TA.

23. Method according to claim 22, characterised in that the tertiary
alcohol is selected from the group consisting of t-butanol, t-amyl
alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol.

24. Method according to claim 22 or 23, characterised in that the protic
solvent is a tertiary diol or polyol.

25. Method according to claim 1, characterised in that it comprises a
purging step in which a non-polar organic solvent, preferably a
hydrocarbon or an alkane, is passed through the column so that to
eliminate most of the remaining water, whilst keeping the extracted
anions trapped on the TA.

26. Method according to claim 25, characterised in that the non-polar
organic solvent is passed through the column until the water content
falls down under 20000 ppm, preferably under 7500 ppm.

27. Method according to claim 25, characterised in that the non-polar
organic solvent is selected from the group consisting of pentane, hexane,
heptane, octane, nonane, decane and cyclohexane.

28. Method according to claim 1, characterised in that it comprises a
drying step in which a flush of gas such as air, nitrogen or argon is
used to purge the column and eliminate most of the remaining water or so
that the water content falls down under 1000 ppm.

29. Method according to claim 28, characterised in that said drying step
is assisted by heating up the SS.

30. Method according to anyone of claims 21 to 29, characterised in that
the dried solid support is used as a means to convey dry [18F] isotopes
from a production center such as a cyclotron to a location where it will
be used for PET radiotracers preparation such as radiopharmacies or
research laboratories.

31. Method according to claim 1, characterised in that the column
containing the extracted [18F] fluoride in a reactive form is used as a
reactor to carry out a subsequent [18F] labelling reaction.

32. Method according to claim 1 or 28, characterised in that, in a further
elution step, a low or no-water content organic solvent is used to
quantitatively elute the TA, among which the TA-[18F] species, from the
SS, said organic solvent being chosen so that the eluted medium is
suitable for an aliphatic or aromatic [18F] labelling reaction without
any further evaporation step, the residual water being lower than 20000
ppm, preferably lower than 7500 ppm, and lower than 1000 ppm when a gas
drying step is performed.

33. Method according to claim 32, characterised in that said organic
solvent is selected from the group consisting of acetonitrile (ACN),
dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF),
dioxane, ethyl acetate, sulfolane, hexamethylphosphotriamide (HMPA/HMPT),
nitromethane and a mix of the latter.

34. Method according to claim 32, characterised in that the solvent used
for the elution process is selected from the group consisting of primary
alcohols such as methanol, ethanol, n-propanol, n-butanol, amyl alcohol,
n-hexyl alcohol, n-heptanol or n-octanol; secondary alcohols such as
isopropanol, isobutanol, isoamyl alcohol, 3-pentanol; and tertiary
alcohols such as t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol,
2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol,
2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol,
2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol,
2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol,
1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol,
1-ethylcyclohexanol, and 1-methylcycloheptanol, the alcohol being more
preferably selected from the group consisting of tertiary alcohols such
as t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol and
2-(trifluoromethyl)-2-propanol.

35. Method according to claim 34, characterised in that the solvent used
for the elution process is a tertiary diol or polyol.

36. Method according to claim 32, characterised in that the solvent used
for the elution process is any mixture of said solvents cited in claims
33 to 35.

37. Method according to claim 11, characterised in that the organic
solvent used to elute the TA from the SS contains a base suitable for the
labelling reaction under the form of said metal, the solubility of the
salt in the organic medium being ensured by a complexing agent selected
from the group consisting of cryptands, glymes, calixarenes,
cyclodextrines and EDTA and its derivatives.

38. Method according to claim 1, characterised in that the organic solvent
used to elute the TA from the SS contains a base under the form of an
ammonium salt, preferably a quaternary ammonium salt, or a base under the
form of an phosphonium salt, preferably a quaternary phosphonium salt.

39. Method according to claim 1, characterised in that the organic solvent
used to elute the TA from the SS contains a base under the form of an
organic base selected from the group consisting of
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 4-Dimethylaminopyridine (DMAP),
1,4-Diazabicyclo[2.2.2]octane (DABCO), 2,6-Lutidine, Pyridine (Py),
alkylamines, dialkylamines, trialkylamines and Diisopropylethylamine
(Hunig's Base).

40. Method according to claim 1, characterised in that the organic solvent
used to elute the TA from the SS contains a base under the form of a
phosphazene base selected from the group consisting of
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospho-
rine, tert-Butylimino-tris(dimethylamino)phosphorane,
1,1,1,3,3,3-Hexakis(dimethylamino)diphosphazenium fluoride,
Imino-tris(dimethylamino)phosphorane, Phosphazene base P1-t-Bu,
Phosphazene base P2-t-Bu, Phosphazene base P4-t-Bu, and
Tetrakis[tris(dimethylamino)phosphoranylidenamino]phosphonium fluoride.

41. Method according to claim 1, characterised in that the organic
solution used to elute the TA is heated up to enhance the elution of the
adsorbed TA, among which the TA-[18F] species.

42. Method according to claim 1, characterised in that a precursor for a
labelling reaction is contained in the organic medium used to elute the
TA.

43. Method according to claim 1, characterised in that trapped ions, among
which the [18F] fluorides, are rinsed out of the column by a saline
aqueous or alcoholic solution, the obtained subsequent solution being
readily injectable after dilution, for specific molecular imaging
indications.

44. Method according to claim 1, characterised in that the organic
solution containing the [18F] fluoride obtained after elution is used for
the synthesis of a PET radiotracer, said [18F] fluoride being reactive
even at room temperature for substitution reactions on both aliphatic and
aromatic precursors.

45. Method according to claim 1, characterised in that a suitable base is
added prior to labelling in the eluted [18F] fluoride solution.

46. Method according to claim 1, characterised in that the same SS can be
reused for an extraction/elution process of a labelled precursor
resulting from a labelling reaction.

47. Method according to claim 46, characterised in that the labelled
precursor trapped on the column is eluted in a suitable solvent prior to
a deprotection reaction.

48. Method according to claim 47, characterised in that the deprotection
reaction is directly performed within the column containing the SS or by
including this column in a reaction circuit.

49. Method according to claim 1, characterised in that said extraction,
concentration and/or reformulation process is preceded by a preliminary
concentration step performed on an additional column comprising an anion
exchange phase such as a quaternary ammonium resin followed by an acid
phase such as a sulfonic or carboxylic resin, the latter to eliminate
detrimental resin preconditioning ions, so that to recover the activity
in a volume reduced by a factor 3 to 40, compatible with the volume of
the modified non-ionic SS column.

Description:

TECHNICAL FIELD

[0001]The present invention relates to a method for the extraction,
concentration and reformulation of the [18F] fluoride contained in water.

BACKGROUND ART

[0002]Positron emission tomography (PET) is an imaging method to obtain
quantitative molecular and biochemical information of physiological
processes in the human body. The most common PET radiotracer in use today
is [18F]-fluorodeoxyglucose ([18F]-FDG), a radiolabelled glucose
molecule. PET Imaging with [18F]-FDG allows to visualize glucose
metabolism and has a broad range of clinical indications. Among positron
emitters, [18F] is the most widely used today in the clinical
environment.

[0003][18F] fluoride is produced by irradiation of water (containing
H218O) with protons resulting in the reaction
18O(p,n)18F. Only a minor fraction of the [18O] is converted.
For production efficiency and radiochemical purity, it is desirable to
use water that is as highly enriched as possible. The physics of the
production of [18F] fluoride by proton bombardment of water (amount of
heat, proton energy range) typically requires, at least 1 mL of water.
The volumes coming out of most cyclotron targets are in practice several
mL.

[0004]The [18F] isotope is then separated from water and processed for
production of a radiopharmaceutical agent. Conventional fluoride recovery
is based on ion exchange resins. The recovery is carried out in two steps
(extraction and elution): first the anions (not only fluoride) are
separated from the enriched [18O] water and trapped on a resin and then,
said anions, including [18F] fluoride, are eluted into a mixture
containing water, organic solvents, a base, also called activating agent
or phase transfer agent or phase transfer catalyst, such as for example
the complex potassium carbonate-Kryptofix 222 (K2CO3-K222) or a
tetrabutylammonium salt. The [18F] fluoride radiochemical recovery yield
is very effective, usually exceeding 99%. The most usual labelling
method, known as nucleophilic substitution, requires anhydrous or very
low water content solutions and whatever the method used, an evaporation
step always follows the recovery of the [18F]fluoride. It usually
consists in multiple azeotropic evaporations of acetonitrile or low
boiling temperature organic solvent, that require several minutes.

AIMS OF THE INVENTION

[0005]The aim of the invention is to simplify and speed up the preparation
of a [18F] fluoride solution suitable for the labelling reaction, i.e.
the substitution reaction, by the use of a modified non-ionic solid
support, which allows to avoid the azeotropic evaporations prior to
labelling.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006]FIG. 1 schematically represents the extraction/elution process for
the [18F] fluoride recovery method which is the object of the invention.
A) Modified solid support (SS) prior to the extraction process, B) [18F]
fluoride trapped on the SS as a TA-[18F] species, C) Bare SS after
elution, TA, among which TA-[18F] species, being released by the elution
solution.

[0007]FIG. 2 and FIG. 3 schematically represent the ammonium salt and the
phosphonium salt respectively, used as trapping agent or as an added base
in the elution solution. R1, R2, R3 and R4, which may be identical or
different substituting groups, are for example hydrogen atoms, alkyl
chains which may comprise from 1 to 30 carbon atoms and especially from 1
to 16 carbon atoms, aryl chains such as benzyl, cycles, like for example
cyclohexane, cyclooctane, or polycycles, like for example naphthalene, a
polymer or any moiety having a chemical function with specific binding
properties toward the solid support.

[0008]If R1, R2, R3 and R4 are alkyl chains, some of these chains may also
be branched on one or several carbon atom(s) of said alkyl chains.
Further, the alkyl chain may be substituted by halogen atoms on one or
several carbon atom(s) of said alkyl chain (for example perfluorinated
alkyl chain).

DISCLOSURE OF THE INVENTION

[0009]The method of the invention allows the preparation of a reactive
fluoride solution for substitution reactions on both aliphatic and
aromatic precursors, without any azeotropic evaporation step. Moreover,
the resulting fluoride ions are made highly reactive even at room
temperature. It brings two advantages: the reduction of the preparation
duration, which results in an increase of the overall yield, and a
simplification of the automated equipment needed for the synthesis of a
radiotracer. In particular, the suppression of any azeotropic evaporation
step facilitates the implementation of the synthesis microfluidic devices
such as "lab-one-chip" in which these evaporations are difficult to
perform.

[0010]According to the present invention, the extraction process is
performed by passing the [18F] aqueous solution on a non-ionic solid
support (SS). As shown on FIG. 1A), this solid support has the
characteristic to be loaded with a trapping agent (TA), which is adsorbed
on the solid support and allows the [18F] activity to be trapped because
of its positive charge. This trapping agent is selected in such a way
that it does not impact unfavorably on the yield of the subsequent
labelling reaction. It is preferably a base suitable for the labelling
reaction. The solid support is then flushed with a gas or a neutral
solvent to remove or push out most of the residual water (FIG. 1B).
Indeed, the remaining water amount is sufficiently low to not be
detrimental for the subsequent labelling step. The activity is at last
eluted in an organic solvent or in a mixture of organic solvents and is
immediately usable for the labelling of aromatic or aliphatic radiotracer
precursors (FIG. 1C)) even at low temperature.

[0011]The present invention is distinguished from prior art by the fact
that the nature of the phase allows the direct elution of the [18F]
activity in a medium suitable for radiolabelling. However, a small amount
of water does neither impact on the recovery yield nor on the
radiochemical yield of the reaction (R. FORTT et al., Proceeding of the
17th International Symposium on Radiopharmaceutical Sciences, Aachen
(Germany), 2007). In the method of prior art, the fluoride is eluted by
an ion exchange method, which is only possible in the presence of a
certain amount of water or in a solvent polar enough to solubilise ions,
which is generally not suitable for the subsequent labelling step. In the
present invention, under the effect of an organic solvent, the fluoride
is eluted by displacement/desorption of the trapping agent adsorbed on
the non-ionic support. The eluting medium may be an organic solution
containing either the said base or the chosen precursor, or a mixture of
them. The [18F] activity is directly in solution and not in a "dry form"
on the surface of a reactor, as it would result from the evaporation step
of prior art. The recovered solution is reactive and immediately usable
for the labelling reactions.

[0012]In the method of prior art, after radiolabelling, the labelled
precursor, which is generally a low polarity compound, is extracted on a
similar solid support as used in the present invention for the [18F]
fluoride recovery step and is subsequently deprotected generally by acid
or basic hydrolysis. Thus, another specific advantage of the method of
the present invention is that the properties of the solid support are
restored after the elution process. Moreover, the same solid support can
be used for both the fluoride ions extraction/elution process and for the
purification, reformulation and deprotection of the labelled precursor
resulting from the labelling reaction.

[0013]According to the present invention, the extraction step of the
method is performed by passing the [18F] aqueous fluoride solution
through a solid phase extraction column containing a modified solid
support. The [18F] fluoride is trapped on the modified solid support.

[0016]In some embodiments of the present invention, the SS is selected
from the group of solid phase extraction resins and liquid chromatography
resins having intermediate polar/non-polar and/or hydrophilic/lipophilic
properties such as graphitized carbon phase. Brand names for these solid
supports are Hypercarb® from Thermo Electron Corp. and Carbograph from
Alltech.

Preferred Embodiment for the Choice of the Couple Solid Support-Trapping
Agent (SS-TA)

[0017]Prior to the [18F] fluoride extraction step a specific preparation
of the SS is performed: a trapping agent (TA) is adsorbed on the SS. The
TA adsorbed on the SS is selected for its ability to trap the [18F]
fluoride by an anion exchange process, forming a TA-[18F] species. The
couple SS-TA is chosen for its specific interaction which allows the TA
to be well-retained on the SS in aqueous media, thus during the
extraction process, while being easily released and solubilized in polar
aprotic solvents suitable for radiolabelling. This is preferably achieved
with phases having these intermediate polar/non-polar and/or
hydrophilic/lipophilic properties, which ensures quantitative
extraction/elution process when the TA is well selected (see Table 1).

[0018]On the polar SS, the TA must be sufficiently polar to remain on the
SS during the extraction, which makes the resulting SS-TA couple
apparently polar and has the tendency to retain too much the water. On
the other hand, for the non-polar SS, the TA must be sufficiently polar
to be eluted from the SS during the elution process with a non-polar
protic solvent, which makes again the resulting SS-TA couple globally
polar and has again the tendency to retain too much the water.
Conversely, SS with intermediate polarity are preferably used, because
these allow the use of less polar TA than polar SS and non-polar SS.
Thus, following the extraction process, efficient water elimination by a
flush with a gas or a neutral solvent is made possible. Indeed, contrary
to what happens on polar SS-TA or non-polar SS-TA couples, the apparent
lowered polarity of the hydrophilic/lipophilic SS-TA couple ease water
elimination.

[0019]Moreover, the TA is selected in such a way that it does not impact
unfavourably on the yield of the subsequent labelling reaction. It is
thus preferably a base positively charged, also called activating agent
or phase transfer agent or phase transfer catalyst, suitable for the
labelling reaction and that can be selected in the group of metal salt
complexes. This complexing agent ensures the trapping of the metal salt
on the SS and its ability to subsequently dissolve in the organic medium.
The complexing agent itself can even behave as TA.

[0020]The metal salt cation is preferably selected from the alkali group
consisting of lithium, sodium, potassium, rubidium, and cesium or from
the alkaline earth metal group consisting of magnesium, calcium,
strontium, and barium. The cation could also be an ammonium
(NH4+).

[0023]In some preferred embodiments of the present invention, the
complexing agent selected for its ability to remain on the SS in aqueous
environment and to be released in an organic environment, suitable for
the subsequent chemistry, is functionalized by a substituting group,
which is for example an alkyl chain which may comprise from 1 to 30
carbon atoms and especially from 1 to 16 carbon atoms, aryl group such as
benzyl, cycles, like for example cyclohexane, cyclooctane, or polycycles,
like for example naphthalene, a polymer or any moiety having a chemical
function with specific binding properties toward the solid support. This
chains may also be branched on one or several carbon atom(s) of said
alkyl chains. Further, the alkyl chain may be substituted by halogen
atoms on one or several carbon atom(s) of said alkyl chain (for example
perfluorinated alkyl chain). Said functional group ensures a good
interaction of the complexing agent with the solid support, while leaving
intact the accessibility of the complexing group.

[0024]The TA can be selected from the group consisting of ammonium salts
and more preferably the quaternary ammonium salts (X--N+R1R2R3R4) as
shown in FIG. 2.

[0025]The TA can also be selected from the group consisting of phosphonium
salts and more preferably the quaternary phosphonium salts
(X--P+R1R2R3R4) as shown in FIG. 3.

[0026]The TA is preferably an asymmetric quaternary ammonium salt as shown
on FIG. 2 or an asymmetric quaternary phosphonium salt as shown on FIG.
3, with R1=R2, R4 being a longer alkyl chain than R1, R2 and R3. This
longer chain is responsible for the hydrophobic interaction of the TA
with the SS. Moreover, this structure favours the accessibility of the
positive charge which is taken into account for a good [18F] fluoride
extraction. More preferably, R1, R2 and R3 are alkyl chains with 1 to 4
carbon atoms and R4 is an alkyl chain with 7 to 18 carbon atoms. The
alkyl chain R1-R4 may also be substituted by halogen atoms on one or
several carbon atom(s) of said alkyl chain (for example perfluorinated
alkyl chain).

[0027]The TA can be selected from the group consisting of sulfonium salts
(X--S+R1R2R3).

[0029]The preparation of the modified SS is performed by adsorbing a metal
salt complex or an ammonium/phosphonium salt or an ionic liquid onto the
SS. In the specific case of the metal salt complexes, the preparation can
be performed in two steps: the first one consists in adsorbing the
complexing agent, the second one being the complexation of the metal salt
by the complexing agent previously trapped on the SS. The type of anion
present on the support can be converted by an anion exchange process on
TA-modified SS.

[0030]In some embodiments of the present invention, after the extraction
process, the column is rinsed with a non-eluting organic solvent that
allows the elimination of the residual water that may be undesirable for
a subsequent chemical processing, whilst keeping the extracted anions
trapped on the TA.

[0031]In some embodiments of the present invention, protic solvents such
as alcohols can be passed through the column to eliminate most of the
remaining water, whilst keeping the extracted anions trapped on the TA.

[0032]In some embodiments of the present invention, the protic solvent is
preferably selected from the group consisting of primary alcohols such as
methanol, ethanol, n-propanol, n-butanol, amyl alcohol, n-hexyl alcohol,
n-heptanol, or n-octanol; secondary alcohols such as isopropanol,
isobutanol, isoamyl alcohol, 3-pentanol; and tertiary alcohols such as
t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol,
2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol,
2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol,
2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol,
2-cyclopropyl-3-methyl-2-butanol, 1 methylcyclopentanol,
1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol,
1-ethylcyclohexanol, and 1-methylcycloheptanol. More preferably the
alcohol is selected from the group consisting of tertiary alcohols such
as t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol and
2-(trifluoromethyl)-2-propanol.

[0033]In some embodiments of the present invention, the protic solvent is
preferably selected from the group consisting of tertiary diols or
polyols, thus with alcohol functions as present on the compound from the
group of tertiary alcohols exemplified above.

[0034]In some embodiments of the present invention, a non-polar organic
solvent, such as an hydrocarbon or an alkane, is passed through the
column to eliminate most of the remaining water, whilst keeping the
extracted anions trapped on the TA.

[0035]In some preferred embodiments of the present invention, the
non-polar organic solvent is selected in the list of pentane, hexane,
heptane, octane, nonane, decane, cyclohexane.

[0036]In some preferred embodiments of the present invention, a flush of
gas such as air, nitrogen or argon can be used to purge the column and
eliminate most of the remaining water, which falls down lower than 20000
ppm, preferably lower than 7500 ppm, the drying method of the present
invention allowing the elimination of water down to 1000 ppm of residual
water in the solution eluted from the column.

[0037]In some embodiments of the invention, this drying step is assisted
by heating-up the SS.

[0038]In some embodiments of the present invention, the dried solid
support can be used as a mean to convey dry [18F] isotopes from a
production center (cyclotron) to the location where it will be used for
PET radiotracer preparation such as radiopharmacies or research
laboratories.

[0039]In some embodiments of the present invention, the column containing
the extracted [18F] fluoride in a reactive form can be used as a reactor
to carry out a subsequent labelling reaction.

[0040]According to the present invention, in a further step, a low or no
water content organic solvent is used to quantitatively elute the TA,
among which the TA-[18F] species, from the SS. The organic solvent is
chosen in such a way that the eluted medium is suitable for the aliphatic
or aromatic labelling reaction without any further evaporation step, the
residual water being lower than 20000 ppm, preferably lower than 7500
ppm, the drying method of the present invention allowing the elimination
of water down to 1000 ppm of residual water in the solution eluted from
the column.

[0041]In some embodiments of the present invention, this organic solvent
can be selected among acetonitrile (ACN), dimethylsulfoxide (DMSO),
dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, ethyl acetate,
sulfolane, hexamethylphosphotriamide (HMPA/HMPT), nitromethane, etc. and
a mix of these solvents.

[0042]In some embodiments of the present invention, the solvent used for
the elution process is selected from the group consisting of primary
alcohols such as methanol, ethanol, n-propanol, n-butanol, amyl alcohol,
n-hexyl alcohol, n-heptanol, or n-octanol; secondary alcohols such as
isopropanol, isobutanol, isoamyl alcohol, 3-pentanol; and tertiary
alcohols such as t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol,
2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol,
2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol,
2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol,
2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol,
1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol,
1-ethylcyclohexanol, and 1-methylcycloheptanol. More preferably the
alcohol is selected from the group consisting of tertiary alcohols such
as t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol and
2-(trifluoromethyl)-2-propanol.

[0043]In some embodiments of the present invention, the solvent used for
the elution process is preferably selected from the group consisting of
tertiary diols or polyols, thus with alcohol functions as present on the
compound from the group of tertiary alcohols exemplified above.

[0044]In some embodiments of the present invention, the solvent used for
the elution process is any mixture of the solvents cited above.

[0045]In some embodiments of the present invention, a base such as a metal
salt, suitable for the labelling reaction, is contained in the organic
solvent used to elute the TA from the SS, the solubility of the salt in
the organic medium being ensured by a complexing agent comprised in the
groups of cryptand, glymes, calixarenes, cyclodextrines and EDTA and its
derivatives.

[0046]In some embodiments of the present invention, the base contained in
the organic solvent used to elute the TA from the SS can be selected in
the group of ammonium salts and more preferably the quaternary ammonium
salts as shown in FIG. 2.

[0047]In some embodiments of the present invention, the base contained in
the organic solvent used to elute the TA from the SS can be selected in
the group of phosphonium salts and more preferably the quaternary
phosphonium salts as shown in FIG. 3.

[0048]In some embodiments of the present invention, the base contained in
the organic solvent used to elute the TA from the SS is preferably
selected from the group consisting of organic bases such as
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 4-Dimethylaminopyridine (DMAP),
1,4-Diazabicyclo[2.2.2]octane (DABCO), 2,6-Lutidine, Pyridine (Py),
alkylamines, dialkylamines, trialkylamines, Diisopropylethylamine
(Hunig's Base).

[0049]In some embodiments of the present invention, the base contained in
the organic solvent used to elute the TA from the SS is preferably
selected from the group consisting of phosphazene bases such as
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospho-
rine, tert-Butylimino-tris(dimethylamino)phosphorane,
1,1,1,3,3,3-Hexakis(dimethylamino)diphosphazenium fluoride,
Imino-tris(dimethylamino)phosphorane, Phosphazene base P1-t-Bu,
Phosphazene base P2-t-Bu, Phosphazene base P4-t-Bu,
Tetrakis[tris(dimethylamino)phosphoranylidenamino]phosphonium fluoride.

[0050]In some embodiments of the present invention the organic solution
used to elute the TA is heated up to enhance the elution of the adsorbed
TA, among which the TA-[18F] species.

[0051]In some embodiments of the present invention, the precursor for the
labelling reaction is contained in the organic medium used to elute the
TA.

[0052]In some embodiments of the invention, the ions among which the [18F]
fluoride, are rinsed out of the column by a saline aqueous or alcoholic
solution. The solution obtained is then readily injectable after
dilution, for specific molecular imaging indications.

[0053]The obtained organic solution containing the [18F] fluoride can be
used for the synthesis of a PET radiotracer. The [18F] fluoride is
reactive, even at room temperature, for substitution reactions on both
aliphatic and aromatic precursors.

[0054]For some specific labelling reactions, a suitable base can be added
prior to labelling in the eluted [18F] fluoride solution.

[0055]An additional advantage of the method of the present invention is
that, for the purification, reformulation and deprotection of the
labelled precursor resulting from the labelling reaction, the same SS as
used for the [18F] fluoride extraction/elution process can be reused,
which results in a simplification of implementation of this method on
automated equipment used for the synthesis of a radiotracer.

[0056]In some embodiment of the present invention, the labelled precursor
trapped on the column is eluted in a suitable solvent prior to a
deprotection reaction.

[0057]In some embodiment of the present invention, said deprotection
reaction, is directly performed within the column containing the SS or by
including this column in a reaction circuit.

Preferred Embodiment for a [18F] Fluoride Preconcentration

[0058]Aiming at the implementation of the method of the current invention
into a miniaturized synthesis system, it is desirable to limit the size
of the modified SS as much as possible in order to elute the activity in
the smallest possible amount of solution for subsequent labelling.
Moreover, the amount of initial [18F] fluoride solution that a given
modified SS can handle is limited by the migration of the TA on the SS.

[0059]On the other hand, the volume of initial aqueous [18F] fluoride
solution delivered by cyclotron systems may vary up to 10 mL or even
beyond, and may exceed the capacity of the modified SS.

[0060]Therefore, a preliminary concentration of the aqueous initial [18F]
fluoride solution can be required to accommodate a wide volume range of
initial aqueous [18F] fluoride solution.

[0061]Such a preconcentration can be advantageously performed on a column
comprising an anion exchange phase, such as a quaternary ammonium resin
like Waters QMA, preconditioned with K2CO3, and an acid phase
such as a sulfonic (like Dowex) or carboxylic resin. The anion exchange
phase allows to recover [18F]-enriched water and the acid phase allows to
transforms carbonates ions, which could be detrimental for the subsequent
said extraction process of the present invention, into carbon dioxide.
The combination of these two solid phases allows to recover the activity
in a volume many times lower (typically 3 to 40 times) and thus
compatible with the volume of the small modified non-ionic solid support
column according to the present invention.

EXAMPLES

[0062]Table 1 below shows the advantages of modified intermediate
polar/non-polar and/or hydrophilic/lipophilic phases (second half of the
table) on the recovery (extraction/elution) of [18F] fluorides from water
in comparison with modified apolar phases (first half of the table).

[0063]Conditioning of the phases: a solution of the trapping agent or the
complexing agent in water or water/organic solvent mixture is used to
condition the solid support. Optionally, the trapping agent or the
complexing agent adsorbed on the support can then be modified by passing
an aqueous salt solution through the column. The column is then rinsed
with pure water.

Example 1

[0064]A 200 μL solution containing 701 μCi of [18F], obtained by
rinsing a cyclotron target with water and diluting it, is passed through
a C8/tetraethylammonium carbonate pre-conditioned column in 12 seconds
using a syringe pump. The activity extracted from the solution and
actually trapped on the column is measured. This allows extracting 92%
(648 μCi) of the activity passed through the column.

Example 2

[0065]A 250 μL solution containing 843 μCi of [18F] is passed
through a C18/tetrabutylammonium carbonate pre-conditioned column in 15
seconds using a syringe pump. The activity extracted from the solution
and actually trapped on the column is measured. This allows extracting
84.6% (713 μCi) of the activity passed through the column.

Example 3

[0066]A 1000 μL solution containing 1325 μCi of [18F] is passed
through a Waters Oasis HLB®/Kryptofix K222/potassium carbonate
pre-conditioned column in 1 minute using a syringe pump. The activity
extracted from the solution and actually trapped on the column is
measured. This allows extracting 98.1% (1300 μCi) of the activity
passed through the column.

Example 4

[0067]A 1000 μL solution containing 1570 μCi of [18F] is passed
through a Thermo Hypercarb®/Tetradecyl-trimethylammonium
bromide/potassium carbonate pre-conditioned column in 1 minute using a
syringe pump. The activity extracted from the solution and actually
trapped on the column is measured. This allows extracting 100% (1570
μCi) of the activity passed through the column.

Example 5

[0068]A 3500 μL solution containing 4253 μCi of [18F] is passed
through a Waters Oasis HLB®/Dodecyl-trimethylammonium
chloride/potassium carbonate pre-conditioned column in 3 minutes using a
syringe pump. The activity extracted from the solution and actually
trapped on the column is measured. This allows extracting 98.8% (4200
μCi) of the activity passed through the column.

Example 6

[0069]A 1000 μL solution containing 993 μCi of [18F] is passed
through a poly(dibenzo-18-crown-6)/potassium carbonate pre-conditioned
column in 1 minute using a syringe pump. The activity extracted from the
solution and actually trapped on the column is measured. This allows
extracting 25% (248 μCi) of the activity passed through the column.

Example 7

[0070]A 1000 μL solution containing 2905 μCi of [18F] is passed
through a Waters Oasis HLB®/dibenzo 18-crown-6/potassium carbonate
pre-conditioned column in 1 minute using a syringe pump. The activity
extracted from the solution and actually trapped on the column is
measured. This allows extracting 33.9% (985 μCi) of the activity
passed through the column.

Example 8

[0071]A 1000 μL solution containing 1046 μCi of [18F] is manually
passed through a C18/polyethyleneglycol 35000/potassium carbonate
pre-conditioned column in 30 seconds. The activity extracted from the
solution and actually trapped on the column is measured. This allows
extracting 28.7% (300 μCi) of the activity passed through the column.

Example 9

[0072]A 2 mL solution of 270 mCi of [18F] fluoride in 18O enriched
water directly coming from the cyclotron target after a
18O(p,n)18F irradiation is passed through a Waters Oasis
HLB®/Kryptofix K222/potassium carbonate pre-conditioned column in 2
minutes using the Helium flush used to purge the target. This allows
extracting 67.8% (183.2 mCi) of the activity passed through the column.

Example 10

[0073]A 2 mL solution of 2.54 mCi of [18F] fluoride in water is passed
through a Baker hydrophilic DVB/trimethyltetradecylammonium carbonate
pre-conditioned column in 30 seconds. This allows extracting 100% (2.54
mCi) of the activity passed through the column.

Examples of Water Elimination from the Columns

Example 11

Drying with a Flush of Nitrogen

[0074]A Baker hydrophilic DVB/trimethyltetradecylammonium carbonate
pre-conditioned column with 2.32 mCi of [18F] fluorides trapped was used.
Water remaining on the column was eliminated using a flush of nitrogen
during 5 minutes. The activity trapped was then eluted in 500 μl of
dry ACN (containing less than 100 ppm of water). The residual water in
the eluted medium was 987 ppm. The elution yield was 94% in this case.

Examples of Elution of the [18F] Fluoride from the Columns

Example 12

Elutions of the Radioactivity from the Above Exemplified Extraction

[0075]All experiments were performed using 1 mL of eluent and with a flow
rate of 1 mL/min (see Table 2).

[0076]Radioactivity extracted on a Waters Oasis HLB®/Kryptofix
K222/potassium carbonate pre-conditioned column is eluted passing 250
μL of a solution of
1,3,4,6-tetraacetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose
and Kryptofix K222 in acetonitrile. This allows eluting 82.7% (1.97 mCi)
of the activity trapped on the column.

Examples of Aliphatic Precursor Labelling

Example 14

[0077]The [18F] fluoride solution obtained from example 10 is heated 10
minutes at 100° C. in presence of potassium carbonate. This allows
the direct labelling of the precursor with a radioTLC yield of 82.2%.

Example 15

[0078]A [18F] fluoride solution eluted by 1 mL of acetonitrile from a
Waters Oasis HLB®/decyltrimethyl-ammonium bromide/potassium carbonate
pre-conditioned column is heated at 95° C. for 10 minutes in
presence of Kryptofix K222, potassium carbonate and
1,3,4,6-tetraacetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose.
This allows the labelling of the precursor with a radioTLC yield of
96.8%. A yield of 98.2% was obtained with 2 minutes of labelling.

Example 16

[0079]A [18F] fluoride solution eluted by 1 mL of acetonitrile from a
Waters Oasis HLB®/decyltrimethyl-ammonium bromide/potassium carbonate
pre-conditioned column is heated at 95° C. for 10 minutes in
presence of Kryptofix K222, 1,8-Diazabicyclo[5.4.0]undec-7-ene and
1,3,4,6-tetraacetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose.
This allows the labelling of the precursor with a radioTLC yield of
98.7%.

Example 17

[0080]A [18F] fluoride solution eluted by 1 mL of acetonitrile from a
Waters Oasis HLB®/decyltrimethyl-ammonium bromide/potassium carbonate
pre-conditioned column is heated at 95° C. for 10 minutes in
presence of Kryptofix K222, potassium carbonate and
(S)--N-{(1-allyl-2-pyrrolidinyl)methyl]-5-(3-toluene-sulfonyloxypropyl)-2-
,3-dimethoxybenzamide. This allows the labelling of the precursor with a
radioTLC yield of 65%.

Examples of Aromatic Precursors Labelling

Example 18

[0081]A [18F] fluoride solution eluted by 1 mL of dimethylsulfoxide from a
Waters Oasis HLB®/decyltrimethyl-ammonium bromide/potassium carbonate
pre-conditioned column is heated at 175° C. for 20 minutes in
presence of 3,4-dimethoxy-2-nitrobenzaldehyde. This allows the labelling
of the precursor with a radioTLC yield of 78.6%.

Example 19

[0082]A [18F] fluoride solution eluted by 1 mL of dimethylsulfoxide from a
Waters Oasis HLB®/decyltrimethylammonium bromide/potassium carbonate
pre-conditioned column is heated at 150° C. for 20 minutes in
presence of Kryptofix K222, potassium carbonate and
benzamide-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-4-nitro-N-2-pyri-
dinyl. This allows the labelling of the precursor with a radioTLC yield of
63.5%.

Example 20

[0083]A [18F] fluoride solution eluted by 1 mL of dimethylsulfoxide from a
Waters Oasis HLB®/decyltrimethyl-ammonium bromide/potassium carbonate
pre-conditioned column is heated at 150° C. for 20 minutes in
presence of Kryptofix K222, potassium carbonate and 6-nitropiperonal.
This allows the labelling of the precursor with a radioTLC yield of
42.2%.

Examples of Precursor Labelling at Room Temperature (RT)

Example 21

[0084]A [18F] fluoride solution eluted by 1 mL of ACN from a Baker
hydrophilic DVB/tetradecyltrimethylammonium carbonate pre-conditioned
column is allowed to react at RT for 20 minutes in presence of 1.4
dinitrobenzene and 500 μL of dried TEAHCO3 in ACN (25 mg/ml).
This allows the labelling of the precursor with a HPLC yield of 43.6%.

Example 22

[0085]A [18F] fluoride solution eluted by 1 mL of ACN from a Baker
hydrophilic DVB/tetradecyltrimethylammonium carbonate pre-conditioned
column is allowed to react at RT for 5 minutes in presence of
1,3,4,6-tetraacetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose.
This allows the labelling of the precursor with a radioTLC yield of
57.5%.

ADVANTAGES OF THE INVENTION

[0086]The phases used in the preferred embodiments of the present
invention, having a mixed polar/non-polar behaviour provide the following
advantages: [0087]quantitative captures on more important water volumes
than with pure non-polar phases as the coexistence of polar and non-polar
moieties favours retention of the transfer agent. Moreover, the
dissymmetry of ammonium (as well as the one of phosphonium and sulfonium)
renders positive groups accessible, the long carbon chain interacting
with the phase; [0088]quantitative elutions as the phase is sufficiently
non-polar to permit to free the pair transfer agent ion-[18F] in an
aprotic polar solvent, also thanks to the accessibility of polar groups
of the transfer agent; [0089]the use of a simple nitrogen flux to
eliminate residual water on the column as well as the use of a solvent
(for example hexane) to rinse water out of the column; [0090]high
labelling rates even at room temperature.